1. Field of the Invention
The invention relates generally to the treatment of lung cancer. More particularly, it relates to certain biological response modifiers and their use in treating neuroendocrine small cell lung cancers and non-neuroendocrine nonsmall cell lung cancers.
2. Description of the Related Art
Lung cancer is a serious public health problem that kills approximately 150,000 people in the United States annually. Minna, J.D., et al. in Cancer, Principles and Practice of Oncology, eds., DeVita, V.T., Jr., et al., Lippincott, Philadelphia (1985), pp. 507-599.
Lung cancers can be grossly divided into small cell lung cancer (SCLC) which accounts for approximately 25% of lung cancer cases and nonsmall cell lung cancer (NSCLC). NSCLC can be further subdivided into adenocarcinoma, lung cell carcinoma and squamus cell carcinoma, each of which account for about 25% of lung cancer cases.
SCLC is caused by a neuroendocrine tumor that undergoes remission generally after chemo- or radiation-therapy but that generally recurs after a few months, after which the patient is usually refractory to these therapeutic modalities. The tumor is initially localized to the lung, but undergoes metastasis to other organs such as the liver, lymph nodes, bone and/or brain. The median survival time of SCLC patients is 1 year.
NSCLC is treated by surgical resection, as well as by chemotherapeutic agents such as cyclophosphamide, methotrexate, ifosfamid and cis-platin. For NSCLC patients, only 25% survive for 5 years after diagnosis.
Clearly, there is a need for newer, more imaginative and more effective therapeutic approaches, such as an approach based upon endogenous biochemical factors that regulate the growth of lung cancer cells that is the subject matter of this invention.
Lung cancer cells make and secrete endogenous growth factors that regulate tumor proliferation. Moody, T., Science, 214:1246 (1981). For example, bombesin/gastrin releasing peptide (BN/GRP), members of a class of peptides referred to as "biological response modifiers" (BRM), are synthesized in SCLC cells as a high molecular weight protein that is processed to a 27-amino acid, biologically active form. Sausville, E.A., et al., J. Biol. Chem., 261:2451 (195). SCLC cells use BN/GRP as an autocrine growth factor
(Cuttitta, F., et al., Nature, 316:823 (1985); these peptides stimulate the clonal growth of such cells. Carney, D.N., et al., Cancer Res., 47:821 (1987). Thus, SCLC cells synthesize and secrete BN/GRP, and BN or GRP bind to cell surface receptors and stimulate the growth of SCLC cells. The autocrine growth cycle of BN/GRP can be blocked using either monoclonal antibodies against BN (Cuttitta et al., 1985) or a BN receptor antagonist, Psi.sup.13, 14 (Leu.sup.14 BN). Mahmoud, S., et al., Life Sci., 44:367 (1989)).
In contrast, NSCLC cells secrete transforming growth factor .alpha. (TGF.alpha.), but not BRMs such as BN/GRP. TGF.alpha. binds to cell surface receptors for epidermal growth factor (EGF), and stimulates growth of NSCLC cells. Imanishi, L., et al., J. Natl. Cancer Inst., 81:220 (1989). Also, EGF stimulates the clonal growth of established NSCLC cell lines such as adenocarcinoma cell line 5M2 (Lee, M., et al., J. Cell Biochem., 1991, in press), and the growth of such NSCLC cells is inhibited by an EGF receptor monoclonal antibody. Moody, T.N., J. Cell. Biochem., 43:139 (1990).
Vasoactive intestinal polypeptide ("VIP"), a 28-amino acid basic peptide BRM of Mr 3324, with the sequence shown in SEQUENCE ID NO: 1) below, is synthesized in normal lung cells, and functions as a bronchodilator. Morice, A.H., et al., Lancet 1:457 (1984). These actions of VIP are mediated by cell surface receptors localized to alveoli and smooth muscle cells. Robberecht, P., et al., Requl. Peptides, 4:241 (1982). VIP receptors have also been identified on human B-lymphocyte cell lines and cells in the peripheral circulation. O'Dorisio, S., et al., J. Immunol., 15:142 (1989). It has recently been found that SCLC and NSCLC cells bind VIP with high affinity. Shaffer, M.M., et al., Peptides, 8:1101 (1987). These observations suggest that VIP, acting through cell surface receptors on normal and malignant lung cells, regulates the growth of such cells. ##STR1##
"Thymosin" is the name given to a class of polypeptide "hormones", isolated from the thymus glands of mammals, that exert profound effects as potentiators of the growth and differentiation of T-lymphocytes. Smith, E.L., et al. Principles of Biochemistry, McGraw-Hill, New York, 1983, Chapter 19. Thymosins can thus be considered to be BRMs. Members of this class include thymosin .alpha.1 ("THN.alpha.1"), a 28-amino acid peptide of 3,108 molecular weight with the following structure SEQ ID NO: 2 ##STR2## (Goldstein, A.L., et al., U.S. Pat. No. 4079127), and with substantial sequence homology to VIP at amino acid positions 4, 5, 7, 20 and 28; thymosin .beta.4 (a 43-amino acid peptide, MW 4982, U.S. Pat. No. 4395404); thymosin .alpha.11 (A 35-amino acid peptide, U.S. Pat. No. 4614731); thymosin .alpha.7 (U.S. Pat. No. 4517119); and, thymosin .beta.3 (a 50-amino acid peptide, U.S. Pat. No. 4395404).
THN.alpha.1 is known to restore cellular immunity to patients with primary immunodeficiency (Frasca, D., et al., Eur. J. Immun., 17:727 (1987)), and, in patients with NSCLC, THN.alpha.1 has been reported to accelerate the reconstitution of thymic dependent immunity. Schulof, R.S., et al., J. Biol. Response Modifiers, 4:147 (1985).
Clinical trials with cancer patients using thymosin Fraction V (a crude mixture of thymosins isolated from thymus glands - Goldstein, A.L., et al., Proc. Nat'l Acad. Sci. USA, 56:1010 (1966), which contains about 0.6% of THN.alpha.1) and THN.alpha.1 itself have yielded equivocal results with regard to the value of immunopotentiation by these polypeptides in the course of the cancers. Thymosin Fraction V in combination with intensive remission-induction chemotherapy in patients with small cell bronchogenic carcinoma reportedly significantly prolonged survival times relative to other treatment groups. Cohen, M.H., et al. J. Am. Med. Assoc., 241:1813 (1979); Johnston-Early, A., et al., J. Am. Med. Assoc., 244:2175 (1980). However, more recently it has been reported that thymosin Fraction V did not influence the outcome in patients with SCLC who were being treated concurrently with induction chemotherapy and radiation therapy (Scher, H.I., et al., Cancer Res., 48:1663 (1988)).
In patients with NSCLC, thymosin Fraction V did not improve the results with vindesine-adriamycin-cis-platin chemotherapy. Valdivieso, M., et al., ASCO Abstracts, C-636 (1981); Bedikian, A.Y., Am. J. Clin. Oncol. (CCT) 7:399 (1984). THN.alpha.1 .alpha.1 itself also failed to influence the course of NSCLC in a small group of patients. Dillman, R.D., et al., J. Biol. Resp. Med., 6:263 (1987). In contrast, in a randomized trial to evaluate the immunorestorative properties of synthetic THN.alpha.1 in postradiation therapy patients with NSCLC, thymosin normalized T-cell function and was associated with significant improvements in relapse-free and overall survival. Schulof, R.S., et al., J. Biol. Resp. Med., 4:147 (1985).
Because of these uncertainties regarding the effects of the thymosins in patients with advanced lung cancers, we have sought, and have found, a more basic and biochemical approach to the inhibition of proliferation of SCLC and NSCLC cells, an approach based on the roles of growth regulation factors operative in lung cancer cells. A new modality for treating SCLC and NSCLC is disclosed and claimed below.